Abstract

An intact hypothalamic-pituitary-adrenal (HPA) axis with effective intracellular glucocorticoid
anti-inflammatory activity is essential for host survival following exposure to an
infectious agent. Glucocorticoids play a major role in regulating the activity of
nuclear factorkappa- B, which has a crucial and generalized role in inducing cytokine
gene transcription after exposure to an invading pathogen. Severe sepsis is, however,
associated with complex alterations of the HPA axis, which may result in decreased
production of cortisol as well as glucocorticoid tissue resistance.

Commentary

Inadequate intracellular glucocorticoid activity, referred to as critical illness-related
corticosteroid insufficiency, typically results in an exaggerated proinflammatory
response [1]. Patients with severe sepsis or septic shock are therefore frequently treated with
exogenous glucocorticoids. While there are large geographic variations in the prescription
of glucocorticoids for sepsis, up to 50% of intensive care unit patients receive such
therapy [2]. Despite over 30 years of investigation and over 20 meta-analyses, the use of glucocorticoids
in patients with sepsis remains extremely controversial and recommendations are conflicting.

The most important recent studies are that of Annane and colleagues [3] and the Corticosteroid Therapy of Septic Shock (CORTICUS) study [4]. Both of these studies have important limitations: 24% patients received etomidate
in the study by Annane and colleagues, whereas 19% received etomidate in the CORTICUS
study. The benefit of steroids in the study by Annane and colleagues may have been
restricted largely to those patients who received etomidate [5]. Furthermore, only patients with 'refractory septic shock' were enrolled in the Annane
study whereas, as a result of an overwhelming selection bias, only approximately 5%
of eligible patients were enrolled in the CORTICUS study [6]. A more recent study found no benefit from a 7-day course of 40 mg of prednisolone
in patients hospitalized with community-acquired pneumonia [7].

In the study by Annane and colleagues [3], patients received 50 mg of hydrocortisone intravenously every 6 hours for 7 days,
whereas in the CORTICUS study [4], patients received this dose for 5 days, followed by a tapering off over a further
5 days. Recently, two longitudinal studies in patients with severe community-acquired
pneumonia found high levels of circulating inflammatory cytokines 3 weeks after clinical
resolution of sepsis [8,9]. These data suggest that patients with severe sepsis may have prolonged immune dysregulation
(even after clinical recovery) and that a longer course of corticosteroids may be
required. The use of a continuous infusion of hydrocortisone has been reported to
result in better glycemic control with less variability of blood glucose concentration
[10]. This may be clinically relevant as it has been demonstrated that an oscillating
blood glucose level is associated with greater oxidative injury than sustained hyperglycemia
[11]. Indeed, a number of reports indicate that glucose variability may be an independent
predictor of outcome in critically ill patients [12]. A continuous infusion of glucocorticoid may, however, result in greater suppression
of the HPA axis. Furthermore, different glucocorticoids differentially affect gene
transcription and have differing pharmacodynamic effects. Consequently, the preferred
glucocorticoid and the optimal dosing strategy in patients with septic shock remain
to be determined.

Evidence-based medicine is defined as the use of the best current scientific evidence
in making decisions about the care of individual patients. Owing to the dearth of
high-level evidence, it is not possible to make strong evidence-based recommendations
on the use of glucocorticoids in patients with sepsis. Therefore, at this juncture,
it is useful to summarize what we know, what we think we know, and what we do not
know in order to lay the foundation for future scientific exploration; this information
is summarized in Table 1.

In summary, the risk/benefit ratio of glucocorticoids should be determined in each
patient. A course (7 to 10 days) of low-dose hydrocortisone (200 mg/day) should be
considered in vasopressor-dependent patients (dosage of norepinephrine or equivalent
of greater than 0.1 μg/kg per minute) within 12 hours of the onset of shock [1]. Steroids should be stopped in patients whose vasopressor dependency has not improved
with 2 days of glucocorticoids. While the outcome benefit of low-dose glucocorticoids
remains to be determined, such a strategy decreases vasopressor dependency and appears
to be safe (no excess mortality, superinfections, or acute myopathy). Infection surveillance
is critical in patients treated with corticosteroids, and to prevent the rebound phenomenon,
the drug should be weaned slowly. At this time, glucocorticoids appear to have a limited
role in patients who have sepsis or severe sepsis and who are at a low risk of dying.